Methods of treating inflammatory pain

ABSTRACT

The invention relates to an anti-CGRP antibody for use in the prevention and/or treatment of inflammatory pain and/or symptoms of inflammatory pain, and to a method of treating and/or preventing inflammatory pain and/or symptoms of inflammatory pain using an anti-CGRP antibody.

This application is a continuation of U.S. patent application Ser. No.14/855,929, filed Sep. 16, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/612,117, filed Feb. 2, 2015, which is acontinuation of U.S. patent application Ser. No. 13/892,130, filed May10, 2013, which is a continuation of U.S. patent application Ser. No.13/621,981 filed Sep. 18, 2012, which is a divisional of U.S. patentapplication Ser. No. 12/920,634 (now U.S. Pat. No. 8,298,536), which isa National Stage Application under 35 U.S.C. §371 of PCT/IB2009/050849,filed on Mar. 3, 2009, which claims the benefit of U.S. PatentApplication No. 61/033,568, filed on Mar. 4, 2008; each of whichapplications is herein incorporated by reference in its entirety for allpurposes.

REFERENCE TO SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. The sequence listing contains no new matter.Said ASCII copy, created on Apr. 21, 2016, is named4430670305SeqList.txt and is 27 Kilobytes in size.

FIELD OF THE INVENTION

The invention relates to an anti-CGRP antibody for use in the preventionand/or treatment of inflammatory pain and/or symptoms of inflammatorypain, and to a method of treating and/or preventing inflammatory painand/or symptoms of inflammatory pain using an anti-CGRP antibody.

BACKGROUND OF THE INVENTION

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact aetiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includefunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

There is a critical medical need to identify new pharmaceutically activecompounds that interfere with key steps of the inflammatory pain processand particularly for the treatment and/or prevention of arthritis painand/or symptoms of arthritis pain.

Surprisingly we have found that administration of an anti-CGRP antibodyis effective in prevention and/or treatment of inflammatory pain,arthritis pain and in particular osteoarthritis pain.

CGRP (calcitonin gene-related peptide) is a 37 amino acid neuropeptidewhich acts as a neurotransmitter in the central nervous system. It bindswith high affinity to the CGRP receptor, Calcitonin receptor-likereceptor (CRLR), activating adenylate cyclase and protein kinase Aproduction.

Centrally penetrating spinally administered, small molecule selectiveCGRP antagonists have been shown to be useful in the treatment ofneuropathic and nociceptive pain conditions (Adwanikar et al, Pain 2007)suggesting that removal of endogenous CGRP in the spinal cord has anantinociceptive effect. Additionally intrathecal administration ofantiserum against CGRP has been shown to reduce nociceptive behaviour inrodent models of arthritis (Kuraishi, Y., et. al Neurosci. lett (1998)92, 325-329).

Surprisingly we have found that administration of an anti-CGRP antibodyis effective, with a peripheral site of action, in the prevention and/ortreatment of inflammatory pain and in particular osteoarthritis painwhen administered peripherally. This peripheral administration routeprovides a distinct advantage over the requirement to administerantibodies intrathecally or spinally, a more high risk and inconvenientproceedure.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides the use of an anti-CGRP antagonistantibody for the manufacture of a medicament for the prevention and/ortreatment of inflammatory pain and/or symptoms of inflammatory pain,wherein the medicament is prepared to be peripherally administered.

The present invention further provides a method of prevention and/ortreatment of inflammatory pain and/or symptoms of inflammatory pain, inan individual, which comprises peripherally administering to saidindividual a therapeutically effective amount of an anti-CGRP antagonistantibody.

In one embodiment, the anti-CGRP antagonist antibody acts peripherallyon administration.

DESCRIPTION OF THE FIGURES

FIG. 1: Osteoarthritis pain model. Antibody G2 was administered at 1 and10 mg/kg, intravenously (1 ml/kg, IV) and, a null antibody (does notbind CGRP) was administered at 10 mg/kg, IV as a negative control. Bothantibodies were dissolved in a vehicle solution containing PBS+0.01%Tween 20. Celecoxib was used as positive control in the study. It wassuspended in 0.5% methylcellulose and 0.025% Tween-20 and wasadministered by oral gavage (1 ml/kg) at 30 mg/kg, twice a daythroughout the study period. Pain responses were assessed on day 2, 3, 7and 10 following initiation of the pharmacology study (day 0) and wereassessed in a fully blinded fashion. Data re the mean±SEM of 6 rats pergroup. *p<0.05 and p<0.01 vs baseline value (Dunnett's test in GraphPadPrism). In the figure, from left to right, bar 1=baseline, bars 2-5=null antibody, bars 6-9=1 mg/ml G2, bars 10-13=10 mg/ml G2, bars14-17=Celecoxib 30 mg/ml.

FIG. 2: Binding assay data demonstrating that antibody G1 inhibits thebinding of α-CGRP to the CGRP1 receptor.

FIG. 3a : serum level of anti-CGRP concentration (ug/ml) vs time afterIV administration of 10 mg/kg, measured by anti-IgG ELISA.

FIG. 3b : serum level of anti-CGRP concentration (ug/ml) vs time afterIV administration of 10, 30, 100 mg/kg, measured by anti-IgG ELISA.

FIG. 4: Alanine scan using a C-terminal CGRP fragment (CGRP 25-37). Thechange in affinity is expressed in fold loss of affinity and which showsthat anti-CGRP antibody G1 binds to the C-terminal region of humanα-CGRP.

FIG. 5: Solution competition by Biacore: CGRP, CGRP fragments orpeptides related in sequence to CGRP were used to determine thespecificity of G1.

FIG. 6: CGRP sequences from human, cynomolgus monkey, rat, mouse , dogand rabbit. Non-conserved residues between species are underlined, theepitope of G1 is in bold.

FIG. 7: Data showing G1 inhibits neurogenic flare in the skin startingfrom 90 min post-treatment. G1 was administered by intravenousadministration (1 ml/kg). Data are from 6-8 or 13 rats per group.*p=0.05, **p=0.01 vs vehicle (phosphate buffered saline) treated groupat each time point (AVOVA).

Table 1: Kd and IC50 of anti-CGRP antibodies measured at 25° C. againsthuman α-CGRP [muMab7E9=murine precursor of G1. Its K_(D) for ratβ-CGRP=1 nM . RN4901=murine tool, recognising same epitope as G1 butshowed same affinities and selectivity in rats (β-CGRP K_(D)=17 nM);G1=antibody humanized from muMab7E9 (K_(D) for rat β-CGRP=0.1 nM).]

Table 2: G1 binding affinities as determined by Biacore

DESCRIPTION OF THE INVENTION

General Techniques

The practice of the present invention will employ, unless otherwiseindicated, conventional techniques of molecular biology (includingrecombinant techniques), microbiology, cell biology, biochemistry andimmunology, which are within the skill of the art. Such techniques areexplained fully in the literature, such as, Molecular Cloning: ALaboratory Manual, second edition (Sambrook et al., 1989) Cold SpringHarbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methodsin Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook(J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I.Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P.Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture:Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell,eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (AcademicPress, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C.Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M.Miller and M. P. Calos, eds., 1987); Current Protocols in MolecularBiology (F. M. Ausubel et al., eds., 1987); PCR: The Polymerase ChainReaction, (Mullis et al., eds., 1994); Current Protocols in Immunology(J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology(Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers,1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D.Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practicalapproach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000);Using antibodies: a laboratory manual (E. Harlow and D. Lane (ColdSpring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer:Principles and Practice of Oncology (V. T. DeVita et al., eds., J. B.Lippincott Company, 1993).

Definitions

An “antibody” is an immunoglobulin molecule capable of specific bindingto a target, such as a carbohydrate, polynucleotide, lipid, polypeptide,etc., through at least one antigen recognition site, located in thevariable region of the immunoglobulin molecule. As used herein, the termencompasses not only intact polyclonal or monoclonal antibodies, butalso fragments thereof (such as Fab, Fab′, F(ab′)₂, Fv, dAb), singlechain antibodies (ScFv), mutants thereof, chimeric antibodies,diabodies, fusion proteins comprising an antibody portion, and any othermodified configuration of the immunoglobulin molecule that comprises anantigen recognition site. An antibody includes an antibody of any class,such as IgG, IgA, or IgM (or sub-class thereof), and the antibody neednot be of any particular class. Depending on the antibody amino acidsequence of the constant domain of its heavy chains, immunoglobulins canbe assigned to different classes. There are five major classes ofimmunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these maybe further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3,IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond tothe different classes of immunoglobulins are called alpha, delta,epsilon, gamma, and mu, respectively. The subunit structures andthree-dimensional configurations of different classes of immunoglobulinsare well known

“Fv” is an antibody fragment that contains a completeantigen-recognition and -binding site. In a two-chain Fv species, thisregion consists of a dimer of one heavy and one light chain variabledomain in tight, non-covalent association. In a single-chain Fv species,one heavy and one light chain variable domain can be covalently linkedby a flexible peptide linker such that the light and heavy chains canassociate in a dimeric structure analogous to that in a two-chain Fvspecies. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding specificity on thesurface of the VH-VL dimer. However, even a single variable domain (orhalf of a Fv comprising only 3 CDRs specific for an antigen) has theability to recognize and bind antigen, although generally at a loweraffinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab' fragmentsdiffer from Fab fragments by the addition of a few residues at thecarboxy terminus of the heavy chain CH1 domain including one or morecysteines from the antibody hinge regions. A F(ab)2 fragment is abivalent fragment comprising two Fab fragments linked by a disulfidebridge at the hinge region.

An antibody can have one or more binding sites (for combining withantigen). If there is more than one binding site, the binding sites maybe identical to one another or may be different. For instance, anaturally-occurring immunoglobulin has two identical binding sites, asingle chain antibody or Fab fragment has one binding site, while a“bispecific” or “bifunctional” antibody (diabody) has two differentbinding sites, in terms of sequence and/or antigen/epitope recognition.

An “isolated antibody” is an antibody that (1) is not associated withnaturally-associated components, including other naturally-associatedantibodies, that accompany it in its native state, (2) is free of otherproteins from the same species, (3) is expressed by a cell from adifferent species, or (4) does not occur in nature.

A “monoclonal antibody” refers to a homogeneous antibody populationwherein the monoclonal antibody is comprised of amino acids (naturallyoccurring and non-naturally occurring) that are involved in theselective binding of an antigen. A population of monoclonal antibodiesis highly specific, being directed against a single antigenic site. Theterm “monoclonal antibody” encompasses not only intact monoclonalantibodies and full-length monoclonal antibodies, but also fragmentsthereof (such as Fab, Fab′, F(ab′)₂, Fv), single chain (ScFv), mutantsthereof, fusion proteins comprising an antibody portion, and any othermodified configuration of the immunoglobulin molecule that comprises anantigen recognition site of the required specificity and the ability tobind to an antigen. It is not intended to be limited as regards to thesource of the antibody or the manner in which it is made (e.g., byhybridoma, phage selection, recombinant expression, transgenic animals,etc.).

As used herein, “humanized” antibodies refer to forms of non-human (e.g.murine) antibodies that are specific chimeric immunoglobulins,immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab′,F(ab′)2 or other antigen-binding subsequences of antibodies) thatcontain minimal sequence derived from non-human immunoglobulin. For themost part, humanized antibodies are human immunoglobulins (recipientantibody) in which residues from a complementarity determining region(CDR) of the recipient are replaced by residues from a CDR of anon-human species (donor antibody) such as mouse, rat, or rabbit havingthe desired specificity, affinity, and biological activity. In someinstances, Fv framework region (FR) residues of the human immunoglobulinare replaced by corresponding non-human residues. Furthermore, thehumanized antibody may comprise residues that are found neither in therecipient antibody nor in the imported CDR or framework sequences, butare included to further refine and optimize antibody performance. Ingeneral, the humanized antibody will comprise substantially all of atleast one, and typically two, variable domains, in which all orsubstantially all of the CDR regions correspond to those of a non-humanimmunoglobulin and all or substantially all of the FR regions are thoseof a human immunoglobulin consensus sequence. The humanized antibodyoptimally also will comprise at least a portion of an immunoglobulinconstant region or domain (Fc), typically that of a humanimmunoglobulin. Antibodies may have Fc regions modified as described inWO 99/58572. Other forms of humanized antibodies have one or more CDRs(one, two, three, four, five, six) which are altered with respect to theoriginal antibody, which are also termed one or more CDRs “derived from”one or more CDRs from the original antibody.

As used herein, “human antibody” means an antibody having an amino acidsequence corresponding to that of an antibody produced by a human and/orhas been made using any of the techniques for making human antibodiesknown in the art or disclosed herein. This definition of a humanantibody includes antibodies comprising at least one human heavy chainpolypeptide or at least one human light chain polypeptide. One suchexample is an antibody comprising murine light chain and human heavychain polypeptides. Human antibodies can be produced using varioustechniques known in the art. In one embodiment, the human antibody isselected from a phage library, where that phage library expresses humanantibodies (Vaughan et al., 1996, Nature Biotechnology, 14:309-314;Sheets et al., 1998, PNAS, (USA) 95:6157-6162; Hoogenboom and Winter,1991, J. Mol. Biol., 227:381; Marks et al., 1991, J. Mol. Biol.,222:581). Human antibodies can also be made by introducing humanimmunoglobulin loci into transgenic animals, e.g., mice in which theendogenous immunoglobulin genes have been partially or completelyinactivated. This approach is described in U.S. Pat. Nos. 5,545,807;5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016.Alternatively, the human antibody may be prepared by immortalizing humanB lymphocytes that produce an antibody directed against a target antigen(such B lymphocytes may be recovered from an individual or may have beenimmunized in vitro). See, e.g., Cole et al., Monoclonal Antibodies andCancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., 1991, J.Immunol., 147 (1):86-95; and U.S. Pat. No. 5,750,373.

A single chain antibody (scFc) is an antibody in which VL and VH regionsare paired to form a monovalent molecule via a synthetic linker thatenables them to be made as a single protein chain (Bird et al Science,242: 423-426 (1988) and Huston et al., Proc. Natl. Acad. Sci. USA,85:5879-5883 (1988)).

Diabodies are bivalent, bispecific antibodies in which VH and VL domainsare expressed on a single polypeptide chain, but using a linker that istooshort to allow for pairing between the two domains on the same chain,thereby forcing the domains to pair with complementary domains ofanother chain and creating two antigen binding sites.

“Chimeric antibodies” refers to those antibodies wherein one portion ofeach of the amino acid sequences of heavy and light chains is homologousto corresponding sequences in antibodies derived from a particularspecies or belonging to a particular class, while the remaining segmentof the chains is homologous to corresponding sequences in another.Typically, in these chimeric antibodies, the variable region of bothlight and heavy chains mimics the variable regions of antibodies derivedfrom one species of mammals, while the constant portions are homologousto the sequences in antibodies derived from another. One clear advantageto such chimeric forms is that, for example, the variable regions canconveniently be derived from presently known sources using readilyavailable hybridomas or B cells from non human host organisms incombination with constant regions derived from, for example, human cellpreparations. While the variable region has the advantage of ease ofpreparation, and the specificity is not affected by its source, theconstant region being human, is less likely to elicit an immune responsefrom a human subject when the antibodies are injected than would theconstant region from a non-human source. However, the definition is notlimited to this particular example.

A “functional Fc region” possesses at least one effector function of anative sequence Fc region. Exemplary “effector functions” include C1qbinding; complement dependent cytotoxicity (CDC); Fc receptor binding;antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis;down-regulation of cell surface receptors (e.g. B cell receptor; BCR),etc. Such effector functions generally require the Fc region to becombined with a binding domain (e.g. an antibody variable domain) andcan be assessed using various assays known in the art for evaluatingsuch antibody effector functions.

A “native sequence Fc region” comprises an amino acid sequence identicalto the amino acid sequence of an Fc region found in nature. A “variantFc region” comprises an amino acid sequence which differs from that of anative sequence Fc region by virtue of at least one amino acidmodification, yet retains at least one effector function of the nativesequence Fc region. Preferably, the variant Fc region has at least oneamino acid substitution compared to a native sequence Fc region or tothe Fc region of a parent polypeptide, e.g. from about one to about tenamino acid substitutions, and preferably from about one to about fiveamino acid substitutions in a native sequence Fc region or in the Fcregion of the parent polypeptide. The variant Fc region herein willpreferably possess at least about 80% sequence identity with a nativesequence Fc region and/or with an Fc region of a parent polypeptide, andmost preferably at least about 90% sequence identity therewith, morepreferably at least about 95% sequence identity therewith.

As used herein “antibody-dependent cell-mediated cytotoxicity” and“ADCC” refer to a cell-mediated reaction in which nonspecific cytotoxiccells that express Fc receptors (FcRs) (e.g. natural killer (NK) cells,neutrophils, and macrophages) recognize bound antibody on a target celland subsequently cause lysis of the target cell. ADCC activity of amolecule of interest can be assessed using an in vitro ADCC assay, suchas that described in U.S. Pat. No. 5,500,362 or 5,821,337. Usefuleffector cells for such assays include peripheral blood mononuclearcells (PBMC) and NK cells. Alternatively, or additionally, ADCC activityof the molecule of interest may be assessed in vivo, e.g., in a animalmodel such as that disclosed in Clynes et al., 1998, PNAS (USA),95:652-656.

As used herein, “Fc receptor” and “FcR” describe a receptor that bindsto the Fc region of an antibody. The preferred FcR is a native sequencehuman FcR. Moreover, a preferred FcR is one which binds an IgG antibody(a gamma receptor) and includes receptors of the FcyRI, FcyRII, andFcyRII) subclasses, including allelic variants and alternatively splicedforms of these receptors. FcyRII receptors include FcyRIIA (an“activating receptor”) and FcyRIIB (an “inhibiting receptor”), whichhave similar amino acid sequences that differ primarily in thecytoplasmic domains thereof. FcRs are reviewed in Ravetch and Kinet,1991, Ann. Rev. Immunol., 9:457-92; Capel et al., 1994, Immunomethods,4:25-34; and de Haas et al., 1995, J. Lab. Clin. Med., 126:330-41. “FcR”also includes the neonatal receptor, FcRn, which is responsible for thetransfer of maternal IgGs to the fetus (Guyer et al., 1976, J. Immunol.,117:587; and Kim et al., 1994, J. Immunol., 24:249).

“Complement dependent cytotoxicity” and “CDC” refer to the lysing of atarget in the presence of complement. The complement activation pathwayis initiated by the binding of the first component of the complementsystem (C1q) to a molecule (e.g. an antibody) complexed with a cognateantigen. To assess complement activation, a CDC assay, e.g. as describedin Gazzano-Santoro et al., J. Immunol. Methods, 202:163 (1996), may beperformed.

As used herein, the terms “G1” and “antibody G1” are usedinterchangeably to refer to an antibody produced by the expressionvectors having deposit numbers ATCC-PTA-6867 and ATCC-PTA-6866. Theamino acid sequence of the heavy chain and light chain variable regionsare shown in SEQ ID Nos. 1 and 2. The CDR portions of antibody G1(including Chothia and Kabat CDRs) are diagrammatically depicted in FIG.5 of WO2007/054809, the content of which is herein incorporated byreference in its entirety.

The polynucleotides encoding the heavy and light chain variable regionsare shown in SEQ ID Nos. 9 and 10. The characterization of antibody G1is described in the Examples of WO2007/054809, the entire content ofwhich is herein incorporated by reference. G1 is a humanized monoclonalblocking antibody (IgG2) which blocks binding and activity of theneuropeptide CGRP (a and b) and its effect of neurogenic vasodilatationcaused by CGRP release. G1 is an IgG2Δa monoclonal anti-CGRP antagonistantibody derived from the murine anti-CGRP antagonist antibodyprecursor, denoted muMAb7E9 as identified in a screen using spleen cellsprepared from a mouse immunized with human and rat CGRP that were fusedwith murine plasmacytoma cells. G1 was created by grafting the muMAb 7E9derived CDRs of light and heavy chain into the closest human germ linesequence followed by the introduction of at least 1 mutation into eachCDR and 2 framework mutations in V_(H). Two mutations were introducedinto the Fc domain of G1 to suppress human Fc-receptor activation. G1and muMab7E9 have been shown to recognise the same epitope.

As used herein, the terms “G2” and “antibody G2” are usedinterchangeably to refer to an anti-rat CGRP mouse monoclonal antibodyas described in Wong HC et al. Hybridoma 12:93-106 (1993). The aminoacid sequence of the heavy chain and light chain variable regions areshown in SEQ ID Nos. 19 and 20. The polynucleotides encoding the heavyand light chain variable regions are shown in SEQ ID Nos. 27 and 28. TheCDR portions of antibody G2 are provided in SEQ ID Nos. 21 to 26. G2 hasbeen shown to recognise the same epitope as G1.

As used herein, “immunospecific” binding of antibodies refers to theantigen specific binding interaction that occurs between theantigen-combining site of an antibody and the specific antigenrecognized by that antibody (i.e., the antibody reacts with the proteinin an ELISA or other immunoassay, and does not react detectably withunrelated proteins).

An epitope that “specifically binds”, or “preferentially binds” (usedinterchangeably herein) to an antibody or a polypeptide is a term wellunderstood in the art, and methods to determine such specific orpreferential binding are also well known in the art. A molecule is saidto exhibit “specific binding” or “preferential binding” if it reacts orassociates more frequently, more rapidly, with greater duration and/orwith greater affinity with a particular cell or substance than it doeswith alternative cells or substances. An antibody “specifically binds”or “preferentially binds” to a target if it binds with greater affinity,avidity, more readily, and/or with greater duration than it binds toother substances. It is also understood by reading this definition that,for example, an antibody (or moiety or epitope) that specifically orpreferentially binds to a first target may or may not specifically orpreferentially bind to a second target. As such, “specific binding” or“preferential binding” does not necessarily require (although it caninclude) exclusive binding. Generally, but not necessarily, reference tobinding means preferential binding.

The terms “polypeptide”, “oligopeptide”, “peptide” and “protein” areused interchangeably herein to refer to polymers of amino acids of anylength. The polymer may be linear or branched, it may comprise modifiedamino acids, and it may be interrupted by non-amino acids. The termsalso encompass an amino acid polymer that has been modified naturally orby intervention; for example, disulfide bond formation, glycosylation,lipidation, acetylation, phosphorylation, or any other manipulation ormodification, such as conjugation with a labeling component. Alsoincluded within the definition are, for example, polypeptides containingone or more analogs of an amino acid (including, for example, unnaturalamino acids, etc.), as well as other modifications known in the art. Itis understood that, because the polypeptides of this invention are basedupon an antibody, the polypeptides can occur as single chains orassociated chains.

“Polynucleotide,” or “nucleic acid,” as used interchangeably herein,refer to polymers of nucleotides of any length, and include DNA and RNA.The nucleotides can be deoxyribonucleotides, ribonucleotides, modifiednucleotides or bases, and/or their analogs, or any substrate that can beincorporated into a polymer by DNA or RNA polymerase. A polynucleotidemay comprise modified nucleotides, such as methylated nucleotides andtheir analogs. If present, modification to the nucleotide structure maybe imparted before or after assembly of the polymer. The sequence ofnucleotides may be interrupted by non-nucleotide components. Apolynucleotide may be further modified after polymerization, such as byconjugation with a labeling component. Other types of modificationsinclude, for example, “caps”, substitution of one or more of thenaturally occurring nucleotides with an analog, internucleotidemodifications such as, for example, those with uncharged linkages (e.g.,methyl phosphonates, phosphotriesters, phosphoamidates, cabamates, etc.)and with charged linkages (e.g., phosphorothioates, phosphorodithioates,etc.), those containing pendant moieties, such as, for example, proteins(e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine,etc.), those with intercalators (e.g., acridine, psoralen, etc.), thosecontaining chelators (e.g., metals, radioactive metals, boron, oxidativemetals, etc.), those containing alkylators, those with modified linkages(e.g., alpha anomeric nucleic acids, etc.), as well as unmodified formsof the polynucleotide(s). Further, any of the hydroxyl groups ordinarilypresent in the sugars may be replaced, for example, by phosphonategroups, phosphate groups, protected by standard protecting groups, oractivated to prepare additional linkages to additional nucleotides, ormay be conjugated to solid supports. The 5′ and 3′ terminal OH can bephosphorylated or substituted with amines or organic capping groupsmoieties of from 1 to 20 carbon atoms. Other hydroxyls may also bederivatized to standard protecting groups. Polynucleotides can alsocontain analogous forms of ribose or deoxyribose sugars that aregenerally known in the art, including, for example, 2′-O-methyl-,2′-O-allyl, 2′-fluoro- or 2′-azido-ribose, carbocyclic sugar analogs,α-anomeric sugars, epimeric sugars such as arabinose, xyloses orlyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclicanalogs and abasic nucleoside analogs such as methyl riboside. One ormore phosphodiester linkages may be replaced by alternative linkinggroups. These alternative linking groups include, but are not limitedto, embodiments wherein phosphate is replaced by P(O)S(“thioate”), P(S)S(“dithioate”), “(O)NR₂ (”amidate“), P(O)R, P(O)OR′, CO or CH₂(”formacetal“), in which each R or R′ is independently H or substitutedor unsubstituted alkyl (1-20 C) optionally containing an ether (—O—)linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not alllinkages in a polynucleotide need be identical. The precedingdescription applies to all polynucleotides referred to herein, includingRNA and DNA.

A “variable region” of an antibody refers to the variable region of theantibody light chain or the variable region of the antibody heavy chain,either alone or in combination. The variable regions of the heavy andlight chain each consist of four framework regions

(FR) connected by three complementarity determining regions (CDRs) alsoknown as hypervariable regions. The CDRs in each chain are held togetherin close proximity by the FRs and, with the CDRs from the other chain,contribute to the formation of the antigen-binding site of antibodies.There are at least two techniques for determining CDRs: (1) an approachbased on cross-species sequence variability (i.e., Kabat et al.Sequences of Proteins of Immunological Interest, (5th ed., 1991,National Institutes of Health, Bethesda Md.)); and (2) an approach basedon crystallographic studies of antigen-antibody complexes (Chothia etal. (1989) Nature 342:877; Al-lazikani et al (1997) J. Molec. Biol.273:927-948)). As used herein, a CDR may refer to CDRs defined by eitherapproach or by a combination of both approaches.

A “constant region” of an antibody refers to the constant region of theantibody light chain or the constant region of the antibody heavy chain,either alone or in combination.

As used herein, an “anti-CGRP antagonist antibody” (interchangeablytermed “anti-CGRP antibody”) refers to an antibody which is able to bindto CGRP and inhibit CGRP biological activity and/or downstreampathway(s). An anti-CGRP antagonist antibody encompasses antibodies thatblock, antagonize, suppress or reduce (including significantly) CGRPbiological activity. For purpose of the present invention, it will beexplicitly understood that the term “anti-CGRP antagonist antibody”encompass all the previously identified terms, titles, and functionalstates and characteristics whereby the CGRP itself, a CGRP biologicalactivity, or the consequences of the biological activity, aresubstantially nullified, decreased, or neutralized in any meaningfuldegree. Examples of anti-CGRP antagonist antibodies are provided herein.

As used herein, “substantially pure” refers to material which is atleast 50% pure (i.e., free from contaminants), more preferably at least90% pure, more preferably at least 95% pure, more preferably at least98% pure, more preferably at least 99% pure.

A “host cell” includes an individual cell or cell culture that can be orhas been a recipient for vector(s) for incorporation of polynucleotideinserts. Host cells include progeny of a single host cell, and theprogeny may not necessarily be completely identical (in morphology or ingenomic DNA complement) to the original parent cell due to natural,accidental, or deliberate mutation. A host cell includes cellstransfected in vivo with a polynucleotide(s) of this invention.

As used herein, “treatment” is an approach for obtaining beneficial ordesired clinical results. For purposes of this invention, beneficial ordesired clinical results include, but are not limited to, one or more ofthe following: improvement or alleviation of any aspect of inflammatorypain and/or symptom of inflammatory pain. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, one or more of the following: including lessening severity,alleviation of pain and/or a symptom associated with inflammatory pain.

An “effective amount” of drug, compound, or pharmaceutical compositionis an amount sufficient to effect beneficial or desired resultsincluding clinical results such as alleviation or reduction in painsensation. An effective amount can be administered in one or moreadministrations. For purposes of this invention, an effective amount ofdrug, compound, or pharmaceutical composition is an amount sufficient totreat, ameliorate, reduce the intensity of and/or prevent inflammatorypain or symptom associated with inflammatory pain. As is understood inthe clinical context, an effective amount of a drug, compound, orpharmaceutical composition may or may not be achieved in conjunctionwith another drug, compound, or pharmaceutical composition.

Thus, an “effective amount” may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable result may be or is achieved.

In one embodiment, “prepared for” herein means the medicament is in theform of a dosage unit or the like suitably packaged and/or marked foruse in peripheral administration.

“Reducing incidence” of inflammatory pain and/or a symptom associatedwith inflammatory pain means any of reducing severity (which can includereducing need for and/or amount of (e.g., exposure to) other drugsand/or therapies generally used for these conditions), duration, and/orfrequency.

“Ameliorating” inflammatory pain and/or a symptom associated withinflammatory pain means a lessening or improvement of one or moresymptoms of inflammatory pain and/or symptoms associated withinflammatory pain as compared to not administering an anti-CGRPantagonist antibody. “Ameliorating” also includes shortening orreduction in duration of a symptom.

“Palliating” inflammatory pain and/or a symptom associated withinflammatory pain means lessening the extent of one or more undesirableclinical manifestations of inflammatory pain in an individual orpopulation of individuals treated with an anti-CGRP antagonist antibodyin accordance with the invention.

As used therein, “delaying” the development of inflammatory pain meansto defer, hinder, slow, retard, stabilize, and/or postpone progressionof inflammatory pain and/or a symptom associated with inflammatory pain.This delay can be of varying lengths of time, depending on the historyof the disease and/or individuals being treated. As is evident to oneskilled in the art, a sufficient or significant delay can, in effect,encompass prevention, in that the individual does not developinflammatory pain. A method that “delays” development of the symptom isa method that reduces probability of developing the symptom in a giventime frame and/or reduces extent of the symptoms in a given time frame,when compared to not using the method. Such comparisons are typicallybased on clinical studies, using a statistically significant number ofsubjects.

A “biological sample” encompasses a variety of sample types obtainedfrom an individual and can be used in a diagnostic or monitoring assay.The definition encompasses blood and other liquid samples of biologicalorigin, solid tissue samples such as a biopsy specimen or tissuecultures or cells derived therefrom, and the progeny thereof. Thedefinition also includes samples that have been manipulated in any wayafter their procurement, such as by treatment with reagents,solubilization, or enrichment for certain components, such as proteinsor polynucleotides, or embedding in a semi-solid or solid matrix forsectioning purposes. The term “biological sample” encompasses a clinicalsample, and also includes cells in culture, cell supernatants, celllysates, serum, plasma, biological fluid, and tissue samples.

An “individual” or “subject” is a vertebrate, preferably a mammal, morepreferably a human. Mammals include, but are not limited to, farmanimals (such as cows), sport animals, pets (such as cats, dogs andhorses), primates, mice and rats.

As used herein, “vector” means a construct, which is capable ofdelivering, and preferably expressing, one or more gene(s) orsequence(s) of interest in a host cell.

Examples of vectors include, but are not limited to, viral vectors,naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors,DNA or RNA expression vectors associated with cationic condensingagents, DNA or RNA expression vectors encapsulated in liposomes, andcertain eukaryotic cells, such as producer cells.

As used herein, “expression control sequence” means a nucleic acidsequence that directs transcription of a nucleic acid. An expressioncontrol sequence can be a promoter, such as a constitutive or aninducible promoter, or an enhancer. The expression control sequence isoperably linked to the nucleic acid sequence to be transcribed.

As used herein, “pharmaceutically acceptable carrier” includes anymaterial which, when combined with an active ingredient, allows theingredient to retain biological activity and is non-reactive with thesubject's immune system. Examples include, but are not limited to, anyof the standard pharmaceutical carriers such as a phosphate bufferedsaline solution, water, emulsions such as oil/water emulsion, andvarious types of wetting agents. Preferred diluents for aerosol orparenteral administration are phosphate buffered saline or normal (0.9%)saline. Compositions comprising such carriers are formulated by wellknown conventional methods (see, for example, Remington's PharmaceuticalSciences, 18th edition, A. Gennaro, ed., Mack Publishing

Co., Easton, Pa., 1990; and Remington, The Science and Practice ofPharmacy 20th Ed. Mack Publishing, 2000).

The term “peripherally administered” as used herein refers to the routeby which the a substance, medicament and/or anti-CGRP antagonistantibody is to be delivered, in particular it means not centrally, notspinally, not intrathecally, not delivered directly into the CNS. Theterm refers to administration routes other than those immediatelyforgoing and includes via a route which is oral, sublingual, buccal,topical, rectal, via inhalation, transdermal, subcutaneous, intravenous,intra-arterial, intramuscular, intracardiac, intraosseous, intradermal,intraperitoneal, transmucosal, vaginal, intravitreal, intra-articular,peri-articular, local or epicutaneous.

The term “acts peripherally” as used herein refers to the site of actionof a substance, compound, medicament and/or anti-CGRP antagonistantibody said site being within the peripheral nervous system as opposedto the central nervous system, said compound, medicament and/oranti-CGRP antagonist antibody said being limited by inability to crossthe barrier to the CNS and brain when peripherally administered. Theterm “centrally penetrating” refers to the ability of a substance tocross the barrier to the brain or CNS.

The term “K_(off)”, as used herein, is intended to refer to the off rateconstant for dissociation of an antibody from the antibody/antigencomplex.

The term “K_(d)”, as used herein, is intended to refer to thedissociation constant of an antibody-antigen interaction.

The present invention is directed to a medicament for the preventionand/or treatment of inflammatory pain and/or symptoms of inflammatorypain and methods for prevention and/or treatment of inflammatory painand/or symptoms of inflammatory pain in an individual.

In a first aspect, the invention provides the use of an anti-CGRPantagonist antibody for the manufacture of a medicament for theprevention and/or treatment of inflammatory pain and/or symptoms ofinflammatory pain, wherein the medicament is prepared for peripheraladministration or wherein the medicament is administered peripherally.

In a second aspect, the invention provides an anti-CGRP antagonistantibody for use in the prevention and/or treatment of inflammatory painand/or symptoms of inflammatory pain wherein the antibody is preparedfor peripheral administration or wherein the antibody is administeredperipherally.

In third aspect, the invention provides the use of an anti-CGRPantagonist antibody for the manufacture of a medicament forameliorating, controlling, reducing incidence of, or delaying thedevelopment or progression of inflammatory pain and/or symptoms ofinflammatory pain, wherein the medicament is prepared for peripheraladministration or wherein the medicament is administered peripherally.

In a fourth aspect, the invention provides a method of preventing and/ortreating inflammatory pain and/or symptoms of inflammatory pain in anindividual, comprising peripheral administration to the individual of aneffective amount of an anti-CGRP antagonist antibody.

In a fifth aspect, the invention provides a method of ameliorating,controlling, reducing incidence of, or delaying the development orprogression of inflammatory pain and/or symptoms of inflammatory pain inan individual, comprising peripheral administration to the individual ofan effective amount of an anti-CGRP antagonist antibody.

According to a preferred embodiment of the present invention theindividual is preferably a mammal, for example a companion animal suchas a horse, cat or dog or a farm animal such as a sheep, cow or pig.Most preferably the mammal is a human.

According to a preferred embodiment of the present invention themedicament and/or anti-CGRP antagonist antibody is prepared for oral,sublingual, buccal, topical, rectal, inhalation, transdermal,subcutaneous, intravenous, intra-arterial, intramuscular, intracardiac,intraosseous, intradermal, intraperitoneal, transmucosal, vaginal,intravitreal, intra-articular, peri-articular, local or epicutaneousadministration.

According to a further preferred embodiment the medicament is isprepared for peripheral administration prior to and/or during and/orafter the development of inflammatory pain.

In one embodiment, the anti-CGRP antagonist antibody acts peripherallyon administration. In one embodiment, the anti-CGRP antagonist antibodyis not administered centrally, spinally or intrathecally.

According to a preferred embodiment of the present invention theinflammatory pain is arthritic pain, which may be rheumatoid arthritispain or osteoarthritis pain. Preferably, the inflammatory pain isosteoarthritis pain.

The uses and methods of the invention may be for improving physicalfunction in an individual having osteoarthritis and/or improvingstiffness in an individual having osteoarthritis.

Diagnosis or assessment of rheumatoid arthritis pain is well-establishedin the art.

Assessment may be performed based on measures known in the art, such aspatient characterization of pain using various pain scales. See, e.g.,Katz et al, Surg Clin North Am. (1999) 79 (2):231-52; Caraceni et al. JPain Symptom Manage (2002) 23(3):239-55. There are also commonly usedscales to measure disease state such as the American College ofRheumatology (ACR) (Felson, et al., Arthritis and Rheumatism (1993)36(6):729-740), the Health Assessment Questionnaire (HAQ) (Fries, etal., (1982) J. Rheumatol. 9: 789-793), the Paulus Scale (Paulus, et al.,Arthritis and Rheumatism (1990) 33: 477-484), and the Arthritis ImpactMeasure Scale (AIMS) (Meenam, et al., Arthritis and Rheumatology (1982)25: 1048-1053).

In one embodiment, ameliorating, controlling, reducing incidence of, ordelaying the development or progression of rheumatoid arthritis painand/or symptoms of rheumatoid arthritis pain is measured by one or moreof ACR, HAQ and AIMS.

Diagnosis or assessment of osteoarthritis pain is also well-establishedin the art.

Assessment may be performed based on measures known in the art, such aspatient characterization of pain using various pain scales. See, e.g.,Katz et al, Surg Clin North Am. (1999) 79 (2):231-52; Caraceni et al. JPain Symptom Manage (2002) 23(3):239-55. For example, WOMAC AmbulationPain Scale (including pain, stiffness, and physical function) and 100 mmVisual Analogue Scale (VAS) may be employed to assess pain and evaluateresponse to the treatment.

In one embodiment, ameliorating, controlling, reducing incidence of, ordelaying the development or progression of osteoarthritis pain and/orsymptoms of osteoarthritis pain is measured by one or more of WOMACAmbulation Pain Scale and VAS.

According to a preferred embodiment of the present invention theanti-CGRP antagonist antibody binds to CGRP, more preferably binds toCGRP and inhibits the ability of CGRP to bind to the CGRP receptor.Preferably the anti-CGRP antagonist antibody binds to both human androdent CGRP, preferably human and rat CGRP. More preferably the antibodybinds to human CGRP, further preferably the anti-CGRP antagonistantibody binds to human α-CGRP or to human α-CGRP and/or β-CGRP. Mostpreferably the anti-CGRP antagonist antibody is an antibody thatexhibits any one or more of the following functional characteristics:(a) binds to CGRP; (b) blocks CGRP from binding to its receptor(s); (c)blocks or decreases CGRP receptor activation, including cAMP activation;(d) inhibits, blocks, suppresses or reduces CGRP biological activity,including downstream pathways mediated by CGRP signalling, such asreceptor binding and/or elicitation of a cellular response to CGRP; (e)prevents, ameliorates, or treats any aspect of inflammatory pain; (f)increases clearance of CGRP; and (g) inhibits (reduces) CGRP synthesis,production or release.

Antibodies of the invention, including G1 and G2, are known to bind CGRPand remove its biological availability for example in the serum thuspreventing CGRP acces to the its receptor and downstream cellularresponses and biological effects of CGRP such as flare and vasodilation.

In a further preferred embodiment of the invention the anti-CGRPantagonist antibody binds to a fragment of CGRP, more preferably to afragment of CGRP as well as to the full length CGRP. Preferably, theanti-CGRP antagonist antibody binds to the C-terminal region or fragmentof CRGP. The C-terminal region or fragment of CRGP preferably comprisesamino acids 19-37 or 25-37 or 29-37 or alternatively 30-37, furtheralternatively 31-37 of CGRP. In a further embodiment, the C-terminalregion or fragment of CRGP preferably comprises amino acids 32-37 mostpreferably 33 to 37 of CGRP. Preferably the CGRP is either α-CGRP orβ-CGRP, further preferably human or rodent, further preferably human orrat, more preferably human, further preferably human α-CGRP or β-CGRP,most preferably human α-CGRP.

In a further preferred embodiment of the invention the anti-CGRPantagonist antibody specifically binds to the amino acid sequence GSKAF.Preferably the sequence GSKAF of CGRP is the epitope to which theanti-CGRP antagonist antibody binds, preferably at position 33 to 37,most preferably the sequence is GXXXF where X can be any amino acid,preferably at positions 33 to 37 of CGRP, the ends defined by aminoacids G33 and F37 of CGRP.

In one embodiment, the present invention provides an anti-CGRPantagonist antibody which specifically binds to an epitope defined byamino acids G33 to F37 of CGRP. The anti-CGRP antagonist antibody mayspecifically bind to the epitope defined by the amino acid sequenceGSKAF. In one embodiment, the present invention provides the use of suchan antibody in the uses and methods defined in the various aspects ofthe present invention.

In one embodiment, the anti-CGRP antagonist antibody inhibits orprevents activation of the CGRP receptor. Preferably the anti-CGRPantibody has an IC50 of between 0.0001 (0.1 nM) to 500 μM. In somepreferred embodiments, the IC50 is between 0.0001 μM and, or is atabout, any of 250 μM, 100 μM, 50 μM, 10 μM, 1 μM, 500 nM, 250 nM, 100nM, 50 nM, 20 nM, 15 nM, 10 nM, 5 nM, 1 nM, or 0.5 nM as measured in anin vitro binding assay. In some further preferred embodiments, IC50 isless than any of 500 pM, or 100 pM, or 50 pM, as measured in an in vitrobinding assay. In a further more preferred embodiment IC50 is 1.2 nM or31 nM.

In a further preferred embodiment, the anti-CGRP antagonist antibodyused is capable of competing with an antibody herein above described forthe binding of CGRP or to a fragment of CGRP, or to a fragment of CGRPas well as the full length CGRP, preferably to the C-terminal region orfragment of CRGP, preferably the C-terminal region or fragment of CRGPcomprises amino acids 19-37 or 25-37 or 29-37 or alternatively 30-37,further alternatively 31-37 of CGRP. In a further embodiment, theC-terminal region or fragment of CRGP preferably comprises amino acids32-37, most preferably 33 to 37 of CGRP.

In a further preferred embodiment, the anti-CGRP antagonist antibody orantigen binding portion thereof as used in the invention is capable ofcompeting with an anti-CGRP antagonist antibody herein above described,in particular G1 or G2 as herein described, for:

-   (a) the binding of CGRP or a fragment of CGRP, or a fragment of CGRP    as well as the full length CGRP, preferably the C-terminal region or    fragment of CRGP, preferably the C-terminal region or fragment of    CRGP comprising amino acids 19-37 or 25-37 or 29-37 or alternatively    30-37, further alternatively 31-37, preferably amino acids 32-37,    most preferably 33 to 37 of CGRP, preferably the CGRP is alpha or    beta, preferably beta, more preferably rodent or human, most    preferably human,-   (b) the binding of the epitope sequence GSKAF, preferably at amino    acid position 33 to 37 of CGRP as defined in (a), more preferably to    the sequence GXXXF, where X is any amino acid, preferably GXXXF at    amino acid position 33 to 37 of CGRP as defined in (a),-   (c) the binding as described in (a) or (b) with substantially the    same Kd and/or substantially the same K_(off), and/or-   (d) binding to CGRP and inhibiting/antagonising CGRP biological    activity and/or downstream pathway(s), preferably the CGRP is alpha    or beta, preferably beta, more preferably rodent or human, most    preferably human.

The anti-CGRP antagonist antibody preferably binds to CGRP, region ofCGRP or fragment of CGRP with a binding affinity (K_(d)) of between0.00001 μM (0.01 nM) to 500 μM. In some preferred embodiments, thebinding affinity (Kd) is between 0.00001 μM and, or is at about, any of250 μM, 100 μM, 50 μM, 10 μM, 1 μM, 500 nM, 250 nM, 100 nM, 50 nM, 20nM, 15 nM, 10 nM, 5 nM, 1 nM, 0.5 nM, 1 nM, 0.05 nM, or 0.01 nM asmeasured in an in vitro binding assay. In some further preferredembodiments, binding affinity (Kd) is less than any of 500 pM, or 100pM, 50 pM, or 10 pM, as measured in an in vitro binding assay. In afurther more preferred embodiment binding affinity (Kd) is 0.04 nM or 16nM.

The anti-CGRP antagonist antibody as used in the present invention maybe selected from the group of: monoclonal antibodies, polyclonalantibodies, antibody fragments (e.g., Fab, Fab′, F(ab′)2, Fv, Fc, ScFvetc.), chimeric antibodies, bispecific antibodies, heteroconjugateantibodies, single chain (ScFv) antibodies, mutants thereof, fusionproteins comprising an antibody portion (e.g., a domain antibody),humanized antibodies, and any other modified configuration of theimmunoglobulin molecule that comprises an antigen recognition site ofthe required specificity, including glycosylation variants ofantibodies, amino acid sequence variants of antibodies, and covalentlymodified antibodies. The anti-CGRP antagonist antibody may be murine,rat, human, or any other origin (including chimeric or humanizedantibodies). In some embodiments, the anti-CGRP antagonist antibody maybe humanized but is more preferably human. Preferably the anti-CGRPantagonist antibody is isolated, further preferably it is substantiallypure. Where the anti-CGRP antagonist antibody is an antibody fragmentthe fragment preferably retains the functional characteristics of theoriginal antibody i.e. the CGRP binding and/or antagonist activity asdescribed in the functional characteristics above.

Examples of anti-CGRP antagonist antibodies are known in the art. Henceaccording to a preferred embodiment of the present invention theanti-CGRP antagonist antibody as used in the present invention ispreferably an anti-CGRP antibody as generally or specifically disclosedin any of (i) WO2007/054809, (ii) WO2007/076336, (iii) Tan et al., Clin.Sci. (Lond). 89:565-73, 1995, (iv) Sigma (Missouri, US), product numberC7113 (clone #4901), (v) Plourde et al., Peptides 14:1225-1229, 1993 orwhich comprises or consists of:

-   (a) a fragment of said antibody (e.g., Fab, Fab′, F(ab′)2, Fv, Fc,    ScFv etc.),-   (b) a light chain of said antibody,-   (c) a heavy chain of said antibody,-   (d) one or more variable region(s) from a light chain and/or a heavy    chain of said antibody,-   (e) one or more CDR(s) (one, two, three, four, five or six CDRs) of    said antibody,-   (f) CDR H3 from the heavy chain of said antibody,-   (g) CDR L3 from the light chain of said antibody,-   (h) three CDRs from the light chain of said antibody,-   (i) three CDRs from the heavy chain of said antibody,-   (j) three CDRs from the light chain and three CDRs from the heavy    chain, of said antibody,-   (k) any one or more of (a) through (j).

According to a preferred embodiment of the present invention theanti-CGRP antagonist antibody is antibody G2 or antibody G1. Accordingto a most preferred embodiment of the present the anti-CGRP antagonistantibody used is the anti-CGRP antibody G1 as specifically disclosed inthe patent application WO2007/054809, or comprising its variants shownin Table 6 of WO2007/054809, also including functionally equivalentantibodies to G1, i.e. comprising conservative substitutions of aminoacid residues or one or more deletions or additions of amino acids whichdo not significantly affect their functional characteristics e.g. CRGPbinding or antagonist activity and variants which have enhanced ordecreased activity and/or binding. As used herein, the terms “G1” and“antibody G1” are used interchangeably to refer to an antibody producedby expression vectors having deposit numbers of ATCC PTA-6867 and ATCCPTA-6866 as disclosed in application WO2007/054809.

According to a further embodiment of the present invention, theanti-CGRP antagonist antibody comprises or consists of a polypeptideselected from: (a) antibody G1 or its variants shown in Table 6 ofWO2007/054809; (b) a fragment or a region of antibody G1 or its variantsshown in Table 6 of WO2007/054809; (c) a light chain of antibody G1 orits variants shown in Table 6 of WO2007/054809; (d) a heavy chain ofantibody G1 or its variants shown in Table 6 of WO2007/054809 (e) one ormore variable region(s) from a light chain and/or a heavy chain ofantibody G1 or its variants shown in Table 6 of WO2007/054809; (f) oneor more CDR(s) (one, two, three, four, five or six CDRs) of antibody G1or its variants shown in Table 6 of WO2007/054809; (g) CDR H3 from theheavy chain of antibody G1 or its variants shown in Table 6 ofWO2007/054809; (h) CDR L3 from the light chain of antibody G1 or itsvariants shown in Table 6 of WO2007/054809; (i) three CDRs from thelight chain of antibody G1 or its variants shown in Table 6 ofWO2007/054809; (j) three CDRs from the heavy chain of antibody G1 or itsvariants shown in Table 6 of WO2007/054809; (k) three CDRs from thelight chain and/or three CDRs from the heavy chain, of antibody G1 orits variants shown in Table 6 of WO2007/054809; and (i) an antibodycomprising any one of (b) through (k). The invention also providespolypeptides comprising any one or more of the above. In someembodiments, the at least one, two, three, four, five, or six CDR(s) areat least about 85%, 86%, 87%, 88%, 89%, 90%, 95%, 96%, 97%, 98%, or 99%identical to at least one, two, three, four, five or six CDRs of G1 orits variants shown in Table 6 of WO2007/054809.

Determination of CDR regions is well within the ability of the skilledperson. It is understood that in some embodiments, CDRs can be acombination of the Kabat and Chothia CDR. In some embodiments, the CDRsare the Kabat CDRs. In other embodiments, the CDRs are the Chothia CDRs.

The anti-CGRP antagonist antibody preferably comprises or consists of afragment or a region of the antibody G1 (e.g., Fab, Fab′, F(ab′)2, Fv,Fc, ScFv etc.) or its variants shown in Table 6 of WO2007/054809.Preferably said fragment or region has the functional characteristics ofan anti-CGRP antagonist antibody for example CGRP binding activityand/or antagonist activity and comprises or consists one or more of alight chain, heavy chain, fragment containing one or more variableregions from a light chain and/or a heavy chain, or one or more CDRsfrom a light chain and/or a heavy chain of the antibody G1.

According to a further preferred embodiment of the invention theanti-CGRP antagonist antibody comprises a light chain variable region,LCVR, comprising a peptide with a sequence selected from the groupconsisting of SEQ ID NOs: 28-32 and/or a heavy chain variable region,HCVR, comprising a peptide with a sequence selected from the groupconsisting of SEQ ID NOs: 34-38 of patent application WO2007/076336.

Further preferably the anti-CGRP antagonist antibody comprises an LCVRpolypeptide of a SEQ ID NO as shown in Table 1 of patent applicationWO2007/076336 and further comprises a HCVR polypeptide of a SED ID NO asshown in Table 1 of patent application WO2007/076336.

According to a further embodiment of the invention the anti-CGRPantagonist antibody used comprises a light chain CDR (CDRL) selectedfrom the group consisting of SEQ ID NOs: 8-13 and/or a heavy chain CDR(CDRH) selected from the group consisting of SEQ ID NOs: 14-22 of patentapplication WO2007/076336.

Methods of making and isolating the anti-CGRP antagonist antibodies ofapplication WO2007/076336 and data demonstrating the CGRP binding andantagonist characterisation of the same are described in applicationWO2007/076336.

Preferably the anti-CGRP antagonist antibody for use in the presentinvention comprises a VH domain that is at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97% at least 98%, at least 99% or 100% identical in amino acidsequence to SEQ ID NO: 1 or SEQ ID NO: 19 presented herein.

Preferably the anti-CGRP antagonist antibody comprises a VL domain thatis at least 85%, at least 86%, at least 87%, at least 88%, at least 89%,at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97% at least 98%, at least 99% or 100%identical in amino acid sequence to SEQ ID NO: 2 or SEQ ID NO: 20presented herein.

The anti-CGRP antagonist antibody preferably comprises a VH domain and aVL domain that are at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97% at least98%, at least 99% or 100% identical in amino acid sequence to SEQ ID NO:1 and 2 respectively or SEQ ID NO: 19 and 20 presented herein,respectively.

Preferably the anti-CGRP antagonist antibody comprises a VH domain thatis at least 90% identical in amino acid sequence to SEQ ID NO: 1 and aVL domain that is at least 90% identical in amino acid sequence to SEQID NO: 2 presented herein.

Alternatively, the anti-CGRP antagonist antibody preferably comprises aVH domain that is at least 90% identical in amino acid sequence to SEQID NO: 19 and a VL domain that is at least 90% identical in amino acidsequence to SEQ ID NO: 20 presented herein.

The anti-CGRP antagonist antibody preferably comprises at least one CDRselected from the group consisting of: (a). CDR H1 as set forth in SEQID NO: 3 or 21; (b). CDR H2 as set forth in SEQ ID NO: 4 or 22; (c). CDRH3 as set forth in SEQ ID NO: 5 or 23;

(d). CDR L1 as set forth in SEQ ID NO: 6 or 24; (e) CDR L2 as set forthin SEQ ID NO: 7 or 25; (f). CDR L3 as set forth in SEQ ID NO: 8 or 26;and (g). variants of CDR L1 , CDR L2 and CDR H2 as shown in Table 6 ofWO2007/054809.

According to a preferred embodiment of the present invention theanti-CGRP antagonist antibody heavy chain constant region may be fromany types of constant region, such as IgG, IgM, IgD, IgA, and IgE; andany isotypes, such as IgG1, IgG2, IgG3, and IgG4.

Further preferably the anti-CGRP antagonist antibody comprises a heavychain produced by the expression vector with ATCC Accession No.PTA-6867. Further preferably the anti-CGRP antagonist antibody comprisesa light chain produced by the expression vector with ATCC Accession No.PTA-6866. Further preferably the anti-CGRP antagonist antibody isproduced by the expression vectors with ATCC Accession Nos. PTA-6867 andPTA-6866.

Preferably the anti-CGRP antagonist antibody for use in the presentinvention is antibody G1 or antibody G2 defined herein.

According to a further embodiment of the invention, the anti-CGRPantagonist antibody comprises a modified constant region as for exampledescribed in WO2007/054809. Preferably the modified constant region isimmunologically inert, including partially immunologically inert, suchthat it does not trigger complement mediated lysis, does not stimulateantibody-dependent cell mediated cytotoxicity (ADCC), does not activatemicroglia. Preferably the modified constant region is reduced in one ormore of these activities. Most preferably the constant region ismodified as described in Eur. J. Immunol. (1999) 29:2613-2624; PCTApplication No. PCT/GB99/01441 and/or UK Patent Application No.9809951.8. According to a preferred embodiment of the invention theanti-CGRP antagonist antibody comprises a human heavy chain IgG2constant region comprising the following mutations: A330, P331 to S330,S331 (amino acid numbering with reference to the wildtype IgG2sequence). Eur. J. Immunol. (1999) 29:2613-2624.

Methods of making and isolating the anti-CGRP antagonist antibodies ofapplication WO2007/054809 and data demonstrating the CGRP binding andantagonist characterisation of the same are described in applicationWO2007/054809. Sequences of SEQ ID No. 1 to 14 of said application areprovided herein as SEQ ID No. 1 to 14, respectively.

According to a further embodiment of the present invention themedicament is prepared for peripheral administration between once to 7times per week, further preferably between once to four times per month,further preferably between once to six times per 6 month period, furtherpreferably once to twelve times per year. Preferably the medicament isprepared to be peripherally administered in a period selected from: oncedaily, once every two, three, four, five or six days, weekly, once everytwo weeks, once every three weeks, monthly, once every two months, onceevery three months, once every four months, once every five months, onceevery six months, once every seven months, once every eight months, onceevery nine months, once every ten months, once every eleven months oryearly. According to preferred embodiments the medicament is prepared tobe peripherally administered via a route selected from one or more of;orally, sublingually, buccally, topically, rectally, via inhalation,transdermally, subcutaneously, intravenously, intra-arterially orintramuscularly, via intracardiac administration, intraosseously,intradermally, intraperitoneally, transmucosally, vaginally,intravitreally ,epicutaneously, intra-articularly, peri-articularly orlocally.

According to a further embodiment of the present invention themedicament is prepared for peripheral administration with an antibodyconcentration of between 0.1 to 200 mg/ml, preferably at about, orbetween 0.1 and about, any one of 0.5, 1, 5, 10,15 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140,150, 160, 170, 180, 190 or 200 mg/ml+/−10% error, most preferably at 50mg/ml.

According to a further embodiment of the present invention themedicament is prepared for peripheral administration with an antibodyconcentration of between 0.1 to 200 mg/kg of body weight; preferably atabout, or between 0.1 and about, any one of 0.5, 1, 5, 10,15 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130,140, 150, 160, 170, 180, 190 or 200 mg/kg of body weight+/−10% error,most preferably at 10 mg/kg.

According to a preferred embodiment of the present invention theanti-CGRP antagonist antibody has a half life in-vivo of more than anyone of 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70,72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104,106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132,134, 136, 138, 140, 142, 144, 146, 148, 150, 152,154, 156, 158, 160,162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188,190, 192, 194, 196, 198, 200, 202, 204, 206, 208 or 210 days+/−1 day,further preferably more than any one of 7, 8, 9, 10, 11, or 12 months.

Preferably the anti-CGRP antagonist antibody has a half life in-vivo ofmore than 6 days.

According to a further preferred embodiment of the present invention,the medicament and/or the anti-CGRP antagonist antibody does not produceeffects of central nervous system and/or cognitive impairment.Preferably the medicament and/or the anti-CGRP antagonist antibody doesnot induce any one ore more of the following: amnesia, confusion,depersonalization, hypesthesia, abnormal thinking, trismus, vertigo,akathisia, apathy, ataxia, circumoral paresthesia, CNS stimulation,emotional lability, euphoria, hallucinations, hostility, hyperesthesia,hyperkinesia, hypotonia, incoordination, libido increase, manicreaction, myoclonus, neuralgia, neuropathy, psychosis, seizure, abnormalspeech, stupor, suicidal ideation; dizziness, somnolence, Insomnia,anxiety, tremor, depression or paresthesia. Most preferably themedicament and/or the anti-CGRP antagonist antibody does not induceimpairment of motor coordination or attention.

According to a further embodiment of the present invention themedicament and/or the anti-CGRP antagonist antibody does not producerespiratory, renal or gastro-intestinal impairment.

According to a further embodiment of the present invention themedicament and/or the anti-CGRP antagonist antibody does not produceeffects of physical and/or psychological dependence. Preferably themedicament and/or the anti-CGRP antagonist antibody does not demonstrateaffinity for opiate, benzodiazepine, phencyclidine (PCP), orN-methyl-D-aspartic acid (NMDA) receptors, or CNS stimulant, or produceany sedating or euphoric effect.

In one embodiment, the anti-CGRP antagonist antibody, on administration,ameliorates, controls, reduces incidence of, or delays the developmentor progression of central pain sensation.

In another embodiment the effect of the anti-CGRP antagonist antibody isequal and/or superior to the effects of NSAIDS and/or opiates in thesame models of inflammatory pain. In one embodiment, the anti-CGRPantagonist antibody is effective in treating refractory painpopulations.

According to a further aspect of the present invention there is providedthe use or method according to any other aspect of the invention whereinthe anti-CGRP antagonist antibody is administered separately,sequentially or simultaneously in combination with one or more furtherpharmacologically active compounds or agents, preferably compounds oragents useful for treating inflammatory pain. Preferably the additionalagent(s) is/are selected from one or more of:

-   (i) an opioid analgesic, e.g. morphine, heroin, hydromorphone,    oxymorphone, levorphanol, levallorphan, methadone, meperidine,    fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone,    propoxyphene, nalmefene, nalorphine, naloxone, naltrexone,    buprenorphine, butorphanol, nalbuphine or pentazocine;-   (ii) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,    diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,    flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,    meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin,    phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac,    cyclooxygenase-2 (COX-2) inhibitors, celecoxib; rofecoxib;    meloxicam, JTE-522; L-745,337; NS398;, or a pharmaceutically    acceptable salt thereof;-   (iii) a barbiturate sedative, e.g. amobarbital, aprobarbital,    butabarbital, butabital, mephobarbital, metharbital, methohexital,    pentobarbital, phenobartital, secobarbital, talbutal, theamylal or    thiopental or a pharmaceutically acceptable salt thereof;-   (iv)a benzodiazepine having a sedative action, e.g.    chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,    oxazepam, temazepam or triazolam or a pharmaceutically acceptable    salt thereof;-   (v) an H₁ antagonist having a sedative action, e.g. diphenhydramine,    pyrilamine, promethazine, chlorpheniramine or chlorcyclizine or a    pharmaceutically acceptable salt thereof;-   (vi)a sedative such as glutethimide, meprobamate, methaqualone or    dichloralphenazone or a pharmaceutically acceptable salt thereof;-   (vii)a skeletal muscle relaxant, e.g. baclofen, carisoprodol,    chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine or a    pharmaceutically acceptable salt thereof;-   (viii)an NMDA receptor antagonist, e.g. dextromethorphan    ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan    ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,    pyrroloquinoline quinone or    cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid or a    pharmaceutically acceptable salt thereof;-   (ix)an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine or    4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquino1-2-yl)-5-(2-pyridyl)    quinazoline;-   (x) a tricyclic antidepressant, e.g. desipramine, imipramine,    amytriptiline or nortriptiline;-   (xi)an anticonvulsant, e.g. carbamazepine or valproate,-   (xii)a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or    NK-1 antagonist, e.g.    (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-dione    (TAK-637),    5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one    (MK-869), lanepitant, dapitant or    3[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine    (2S,3S);-   (xiii)a muscarinic antagonist, e.g oxybutin, tolterodine,    propiverine, tropsium chloride or darifenacin;-   (xiv)a COX-2 inhibitor, e.g. celecoxib, rofecoxib or valdecoxib;-   (xv)a non-selective COX inhibitor (preferably with GI protection),    e.g. nitroflurbiprofen (HOT-1026),-   (xvi)a coal-tar analgesic, in particular paracetamol;-   (xvii)a neuroleptic such as droperidol;-   (xviii)a vanilloid receptor agonist (e.g. resinferatoxin) or    antagonist (e.g. capsazepine);-   (xix) a beta-adrenergic such as propranolol;-   (xx) a local anaesthetic, such as mexiletine;-   (xxi) a corticosteriod, such as dexamethasone;-   (xxii) a serotonin receptor agonist or antagonist;-   (xxiii) a cholinergic (nicotinic) analgesic;-   (xxiv) Tramadol (trade mark);-   (xxv) a PDEV inhibitor, such as sildenafil, vardenafil or taladafil;-   (xxvi) an alpha-2-delta ligand such as gabapentin or pregabalin;-   (xxvii) a canabinoid; and-   (xxviii) an antidepressant, such as amitriptyline (Elavil),    trazodone (Desyrel), and imipramine (Tofranil) or anticonvulsants    such as phenytoin (Dilantin) or carbamazepine (Tegretol).

According to a further aspect of the present invention there is provideda pharmaceutical composition for the prevention and/or treatment ofinflammatory pain and/or symptoms of inflammatory pain or forameliorating, controlling, reducing incidence of, or delaying thedevelopment or progression of inflammatory pain and/or symptoms ofinflammatory pain in an individual, comprising an anti-CGRP antagonistantibody and a pharmaceutically acceptable carrier and/or an excipient,wherein the composition is prepared to be peripherally administered.

According to a further aspect of the present invention there is provideda kit comprising:

-   (a) a pharmaceutical composition as defined above; and-   (b) instructions for the peripheral administration of an effective    amount of said pharmaceutical composition to an individual for the    prevention and/or treatment of inflammatory pain and/or symptoms of    inflammatory pain or for ameliorating, controlling, reducing    incidence of, or delaying the development or progression of    inflammatory pain and/or symptoms of inflammatory pain.

The kit may include one or more containers containing an anti-CGRPantagonist antibody or polypeptide described herein and instructions foruse in accordance with any of the methods and uses of the invention. Thekit may further comprise a description of selecting an individualsuitable for treatment based on identifying whether that individual hasinflammatory pain or is at risk of having inflammatory pain. Theinstructions for the peripheral administration of the pharmaceuticalcomposition may include information as to dosage, dosing schedule androutes of administration for the intended treatment.

Preferred features of each aspect of the invention apply equally to eachother aspect mutatis mutandis.

EXAMPLES

The present invention is now described with reference to the followingExamples which are intended to illustrate but not to limit theinvention.

The following examples and figures are made with reference to antibodyG1, an anti-human CGRP human monoclonal antibody; and to antibody G2, ananti-rat CGRP mouse monoclonal antibody (Wong H C et al. Hybridoma12:93-106 (1993)).

Example 1 Osteoarthritis (OA) Mechanistic Pain Models (Transection ofthe Medial Meniscus (MMT))

Transection of the medial meniscus (MMT) in one hind knee of the ratresults in the development of cartilage lesions and other changes in thejoint similar to those that occur in OA. The resulting joint pain leadsto the development of sustained changes in weight bearing (assessedusing an incapacitance meter) in the rat hind limbs and mechanical(tactile) allodynia (assessed using von Frey filaments), in the hindpaw, lasting several weeks. Studies were carried out accordingly to ablind protocol, where the investigator was not aware of the identity ofthe compound/control or the treatment of the animal.

Antibody G2 (an anti-CGRP monoclonal antibody) reversed weight bearingdeficit of the OA hind limb at the highest dose tested, 10 mg/kg, IV.Its effect was comparable to celecoxib. Both compounds reversed theshift in weight bearing on the OA limb to normal value. No effect wasseen with the lower dose. This effect lasted 10 days post administrationwhen the plasma exposure of antibody G2 achieved an average value of65.1±3 ug/ml (6.3±0.3 ug/ml, for the lower dose at 10 days post IV).

The negative control, null antibody, i.e. does not bind CGRP,(see FIG.1), demonstrated an effect on weight bearing at the early time points.This effect was unexpected and cannot be explained, but was notsustained and not observed on the allodynia end points (FIG. 1).

Repeat experiments under the same conditions using a buffer as negativecontrol showed no effect on weight bearing for the negative control andreversed the shift in weight bearing on the OA limb to normal value forG1.

Example 2 Binding Assay

A binding assay was performed to measure the IC₅₀ of anti-CGRP antibodyG2 and G1 in blocking human α-CGRP from binding to the CGRP1-receptor inSK-N-MC cells. Dose response curves were plotted and K_(i) values weredetermined using the equation: K_(i)=IC₅₀/(1+([ligand]/K_(D)); FIG. 2,where the equilibrium dissociation constant K_(D)=0.37 nM for humanα-CGRP to CGRP1-receptor as present in SK-N-MC cells. The reported IC₅₀value (in terms of IgG molecules) was converted to binding sites so thatit could be compared with the affinities (K_(D)) determined by Biacoreusing N-biotinylated human and rat α-CGRPs were captured on individualflow cells at low levels (typically 100 response units) to provide thereaction surfaces, while an unmodified flow cell served as a referencechannel. G1 was titrated over the chip surface Binding affinities werededuced from the quotient of the kinetic rate constants(K_(D)=k_(off)/k_(on)) see Table 1.

TABLE 1 G2 Mouse Mab 7E9 G1 KD (nM), α-Hu 17 1.0 0.04 IC50 (nM) α-Hu 372.6 1.2 KD (nM) α-Rat 1.0 58 1.2

TABLE 2 N-biotin-CGRP on chip ° C. k_(on) (1/Ms) k_(off) (1/s) T_(1/2)(h) K_(D) (nM) α-human 25 1.86 × 10⁵ 7.80 × 10⁻⁵ 24.68 0.042 α-human 375.87 × 10⁵ 3.63 × 10⁻⁵ 5.30 0.063 β-human 37 4.51 × 10⁵ 6.98 × 10⁻⁵ 2.760.155 α-rat 25 5.08 × 10⁴ 6.18 × 10⁻⁵ 3.12 1.22 α-rat 37 1.55 × 10⁵ 3.99× 10⁻⁴ 0.48 2.57 β-rat 37 5.16 × 10⁵ 7.85 × 10⁻⁵ 2.45 0.152

Binding affinity of G1 for human α and β CGRP was equivalent (Kd=0.155and 0.152 nM respectively). Binding affinity of G2 for rat α and β CGRPwas equivalent (16 and 17 nM, respectively). Additionally G1 bindingaffinity is 40-fold more potent in human than rat for α-CGRP (Kd=0.042and 1.22 nM, respectively) and equi-potent in human and rat for β-CGRP(Kd=0.155 and 0.152 nM, respectively). Antibody G1 also demonstratedgood cross species selectivity and binds rat α-CGRP with the sameaffinity as antibody G2 (around 1.2 nM) Table 2.

G1 binds human and cynomolgus monkey α- and β-CGRP with high affinity(K_(D)=63 and 155 pM, respectively). G1 displays species selectivity forhuman/cyno CGRP and binds α- and β-CGRP from other species e.g. rat withlower affinity (K_(D)=2.57 nM and 152 pM, respectively).

Example 3 Half Life of Anti-CGRP In-Vivo

Serum measurements of anti-CGRP in rat, FIG. 3, indicate that the halflife is of the order of 7 days. The antibody is peripherally restrictedhaving a molecular weight of around 150,000, FIGS. 3a, 3b , i.e. it doesnot cross into the central nervous system or cross the blood brainbarrier.

Example 4 Selectivity of Anti-CGRP Antibody

We determined the specificity of antibody G1 to human or rat CGRP byusing the Biacore chip to “probe” the free concentration of a premixedcomplex of mAb+peptide. As expected when we pre-incubated antibody G1with human or rat CGRP the response was fully blocked. In contrastpre-incubating G1, with an excess of amylin, calcitonin oradrenomedullin was comparable to the control response (G1 plus buffer)demonstrating that G1 did not form a complex with these peptides (FIG.5).

Example 5 Identification of Antibody GI Binding Epitope

Interaction analysis was conducted at 25° C. on a Biacore 3000™ systemequipped with streptavidin-coated (SA) sensor chips (Biacore AB,Uppsala, Sweden) using a standard Biacore running buffer (HBS-P). Firstwe confirmed that an N-biotinylated 25-37 human α-CGRP fragment boundwith the same affinity to antibody G1, as full-length N-biotinylatedhuman α-CGRP. Each amino acid between position 27-37 was then mutatedindividually to alanine and expressed the fold loss in affinity comparedto the wild-type fragment. N-biotinylated fragments were captured onindividual flow cells at low levels (typically 100 response units) toprovide the reaction surfaces, while an unmodified flow cell served as areference channel. Purified Fab fragments of antibody G1 were generated.Fab fragments were titrated over the chip using 1 μM as the topconcentration of a two-fold dilution series. Association anddissociation phases were monitored at 100 μl/min for 1 minute and 5minutes respectively. Surfaces were regenerated with a mixture of 35%ethanol+25 mM NaOH+0.5 M NaCl.

The alanine scan results show that antibody G1 binds to the C-terminalregion of human α-CGRP, particularly residues 25 to 37, and showsspecific binding to a region (i.e. loss of affinity is markedlyincreased when the specific binding region is mutated) which can bedefined as the epitope and which lies within the last 5 C-terminal aminoacids, i.e. from G33A to F37A. Most profound changes in affinity arecaused through the G33A and F37A mutation (FIG. 4). C-terminal Phe isimportant for selectivity of antibody G1 for CGRP vs related peptidesand gene family members (FIG. 6).

Thus, in one embodiment, the present invention provides an anti-CGRPantagonist antibody which specifically binds to an epitope defined byamino acids G33 to F37 of CGRP. The anti-CGRP antagonist antibody mayspecifically bind to the epitope defined by the amino acid sequenceGSKAF, more specifically to the epitope of CGRP is defined as GXXXFwhere X can be any amino acid, the G33 and F37 being the most importantresidues of the epitope for defining high affinity binding of theanti-CGRP antagonist antibody.

Example 6 Analysis of Indicators of Physical or Psychological Dependence

Neither antibody G1 nor antibody G2 demonstrate CNS penetration.Additionally long term observation of animals (rats) dosed with eitherantibody to levels used in the previous examples did not reveal adverseCNS events such as sedation or stimulation/euphoric behaviour incomparison to control animals. These observations indicate an absence ofdependency risk for the antibodies and hence a significantly improvedsafety of the antibodies over current opiates used in current paintherapies.

Example 7 Analysis of Indicators of Gastro-Intestinal Adverse Effects

A 1 month in-vivo rat study with antibody G2 and 1 week comparativestudy with antibody G1 demonstrated that no adverse gastro intestinaleffects were observed on behaviour, food intake, stool production orhistopathology in comparison to control animals. These observationsindicate an absence of gastrointestinal risk for the antibodies andhence a significantly improved safety of the antibodies over currentNSAIDs used in current pain therapies.

Example 8 G1 and G2 as Anti-CGRP Antagonist Antibodies

A known consequence of CGRP biological activity is the generationneurogenic flare when delivered in vivo. G1 and G2 are demonstrated tobe anti-CGRP antagonist antibodies in that they prevent the developmentof neurogenic flare in vivo.

Using a neurogenic skin flare rat model the efficacy of G1 was testedfor its ability to block CGRP effect in vivo. The saphenous nerve in therat is electrically stimulated causing CGRP release from nerve endingsand leading to vasodilation, the resulting changes in blood flow can bemeasured using laser Dopler methods.

Changes in blood flow parameters were expressed as the area under thecurve (AUC, change in arbitrary Doppler flux units multiplied by time).CGRP receptor antagonist CGRP₈₋₃₇ (400 nmol/kg, i.v.) was used as apositive control to validate the specificity of the model (data notshown). To determine the effect of G1 prior to dosing for each animal,the baseline blood flow response to stimulation was established with twosaphenous nerve stimulations each 30 minutes apart. Rats were treatedwith G1 after the blood flow response of the second stimulation hadreturned to baseline levels (approximately 10 minutes post stimulation)and an additional four stimulations at 30 minute intervals wereperformed.

Results (FIG. 7) demonstrated that in vehicle treated animals nosignificant change in blood flow response was but rats treated with G1showed a significant decrease in blood flow response starting at 90 and120 minutes post dose for 10 mg/kg and 1 mg/kg, respectively. Similaractivity was achieved using D2. Additionally in further neurogenic flareand vasodilatation model tests G1 showed marked effect at 7 days post IVdosing (predicted ED₅₀₌6 ug/ml in saphenous nerve stimulation model).The conclusions form the tests done is that G1 and G2 demonstrateanti-CGRP antagonist activity. Similar CGRP function-blocking abilityfor the antibodies is also shown in the publication, Zeller J, et. al.Br J Pharmacol. 2008 Dec; 155(7): 1093-103. Epub 2008 Sep 8.

Below are given antibody sequences useful for practising the presentinvention.

Antibody Sequences

Antibody G1 heavy chain variable region amino acid sequence (SEQ ID NO: 1)EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASATHYAEAVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQG TLVTVSSAntibody G1 light chain variable region amino acid sequence (SEQ ID NO: 2)EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCSQSYNYPYTFGQGTKLEIKAntibody G1 CDR H1 (extended CDR) (SEQ ID NO: 3) GFTFSNYWISAntibody G1 CDR H2 (extended CDR) (SEQ ID NO: 4) EIRSESDASATHYAEAVKGAntibody G1 CDR H3 (SEQ ID NO: 5) YFDYGLAIQNYAntibody G1 CDR L1 (SEQ ID NO: 6) KASKRVTTYVSAntibody G1 CDR L2 (SEQ ID NO: 7) GASNRYLAntibody G1 CDR L3 (SEQ ID NO: 8) SQSYNYPYTAntibody G1 heavy chain variable region nucleotide sequence (SEQ ID NO: 9)GAAGTTCAGCTGGTTGAATCCGGTGGTGGTCTGGTTCAGCCAGGTGGTTCCCTGCGTCTGTCCTGCGCTGCTTCCGGTTTCACCTTCTCCAACTACTGGATCTCCTGGGTTCGTCAGGCTCCTGGTAAAGGTCTGGAATGGGTTGCTGAAATCCGTTCCGAATCCGACGCGTCCGCTACCCATTACGCTGAAGCTGTTAAAGGTCGTTTCACCATCTCCCGTGACAACGCTAAGAACTCCCTGTACCTGCAGATGAACTCCCTGCGTGCTGAAGACACCGCTGTTTACTACTGCCTGGCTTACTTTGACTACGGTCTGGCTATCCAGAACTACTGGGGTCAGGGTACCCTGGTTACCGTTTCCTCCAntibody G1 light chain variable region nucleotide sequence (SEQ ID NO: 10)GAAATCGTTCTGACCCAGTCCCCGGCTACCCTGTCCCTGTCCCCAGGTGAACGTGCTACCCTGTCCTGCAAAGCTTCCAAACGGGTTACCACCTACGTTTCCTGGTACCAGCAGAAACCCGGTCAGGCTCCTCGTCTGCTGATCTACGGTGCTTCCAACCGTTACCTCGGTATCCCAGCTCGTTTCTCCGGTTCCGGTTCCGGTACCGACTTCACCCTGACCATCTCCTCCCTGGAACCCGAAGACTTCGCTGTTTACTACTGCAGTCAGTCCTACAACTACCCCTACACCTTCGGTCAGGGTACCAAACTGGAAATCAAAAntibody G1 heavy chain full antibody amino acid sequence (including modified IgG2 asdescribed herein) (SEQ ID NO: 11)EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWISWVRQAPGKGLEWVAEIRSESDASATHYAEAVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCLAYFDYGLAIQNYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKAntibody G1 light chain full antibody amino acid sequence (SEQ ID NO: 12)EIVLTQSPATLSLSPGERATLSCKASKRVTTYVSWYQQKPGQAPRLLIYGASNRYLGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCSQSYNYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECAntibody G1 heavy chain full antibody nucleotide sequence (including modified IgG2 asdescribed herein) (SEQ ID NO: 13)GAAGTTCAGCTGGTTGAATCCGGTGGTGGTCTGGTTCAGCCAGGTGGTTCCCTGCGTCTGTCCTGCGCTGCTTCCGGTTTCACCTTCTCCAACTACTGGATCTCCTGGGTTCGTCAGGCTCCTGGTAAAGGTCTGGAATGGGTTGCTGAAATCCGTTCCGAATCCGACGCGTCCGCTACCCATTACGCTGAAGCTGTTAAAGGTCGTTTCACCATCTCCCGTGACAACGCTAAGAACTCCCTGTACCTGCAGATGAACTCCCTGCGTGCTGAAGACACCGCTGTTTACTACTGCCTGGCTTACTTTGACTACGGTCTGGCTATCCAGAACTACTGGGGTCAGGGTACCCTGGTTACCGTTTCCTCCGCCTCCACCAAGGGCCCATCTGTCTTCCCACTGGCCCCATGCTCCCGCAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCAGAACCTGTGACCGTGTCCTGGAACTCTGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTGCAGTCCTCAGGTCTCTACTCCCTCAGCAGCGTGGTGACCGTGCCATCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCACAAGCCAAGCAACACCAAGGTCGACAAGACCGTGGAGAGAAAGTGTTGTGTGGAGTGTCCACCTTGTCCAGCCCCTCCAGTGGCCGGACCATCCGTGTTCCTGTTCCCTCCAAAGCCAAAGGACACCCTGATGATCTCCAGAACCCCAGAGGTGACCTGTGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGCAGTTCAACTGGTATGTGGACGGAGTGGAGGTGCACAACGCCAAGACCAAGCCAAGAGAGGAGCAGTTCAACTCCACCTTCAGAGTGGTGAGCGTGCTGACCGTGGTGCACCAGGACTGGCTGAACGGAAAGGAGTATAAGTGTAAGGTGTCCAACAAGGGACTGCCATCCAGCATCGAGAAGACCATCTCCAAGACCAAGGGACAGCCAAGAGAGCCACAGGTGTATACCCTGCCCCCATCCAGAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGATTCTATCCATCCGACATCGCCGTGGAGTGGGAGTCCAACGGACAGCCAGAGAACAACTATAAGACCACCCCTCCAATGCTGGACTCCGACGGATCCTTCTTCCTGTATTCCAAGCTGACCGTGGACAAGTCCAGATGGCAGCAGGGAAACGTGTTCTCTTGTTCCGTGATGCACGAGGCCCTGCACAACCACTATACCCAGAAGAGCCTGTCCCTGTCTCCAGGAAAGTAAAntibody G1 light chain full antibody nucleotide sequence (SEQ ID NO: 14)GAAATCGTTCTGACCCAGTCCCCGGCTACCCTGTCCCTGTCCCCAGGTGAACGTGCTACCCTGTCCTGCAAAGCTTCCAAACGGGTTACCACCTACGTTTCCTGGTACCAGCAGAAACCCGGTCAGGCTCCTCGTCTGCTGATCTACGGTGCTTCCAACCGTTACCTCGGTATCCCAGCTCGTTTCTCCGGTTCCGGTTCCGGTACCGACTTCACCCTGACCATCTCCTCCCTGGAACCCGAAGACTTCGCTGTTTACTACTGCAGTCAGTCCTACAACTACCCCTACACCTTCGGTCAGGGTACCAAACTGGAAATCAAACGCACTGTGGCTGCACCATCTGTCTTCATCTTCCCTCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCGCGCGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCCGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACCCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCTCCAGTCACAAAGAGCTTCAACCGCGGTGAGTGCTAAAmino acid sequence comparison of human and rat CGRP (human α-CGRP (SEQ IDNO: 15); human β-CGRP (SEQ ID NO: 16); rat α-CGRP (SEQ ID NO: 17); and rat β-CGRP (SEQ ID NO: 18)):

  (SEQ ID NO: 15)

 (SEQ ID NO: 16)

 (SEQ ID NO: 17)

 (SEQ ID NO: 18)Antibody G2 heavy chain variable region amino acid sequence (SEQ ID NO: 19)EVQLQQSGPELVKPGASVKMSCKASGYTFTSSVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCAKGGNDGYWGQGTTLTVSSAntibody G2 light chain variable region amino acid sequence (SEQ ID NO: 20)EIVLTQSPTTMAASPGEKITITCSASSSISSIYLHWYQQKPGFSPKVLIYRASNLASGVPARFSGSGSGTSYSLTIGTMEAEDVATYYCQQGSTIPFTFGSGTKLEIKAntibody G2 CDR H1 (extended CDR) (SEQ ID NO: 21) SSVMHAntibody G2 CDR H2 (extended CDR) (SEQ ID NO: 22) YINPYNDGTKYNEKFKGAntibody G2 CDR H3 (SEQ ID NO:23) GGNDGYAntibody G2 CDR L1 (SEQ ID NO: 24) SASSSISSIYLHAntibody G2 CDR L2 (SEQ ID NO: 25) RASNLASAntibody G2 CDR L3 (SEQ ID NO: 26) QQGSTIPFTAntibody G2 heavy chain variable region nucleotide sequence (SEQ ID NO: 27)GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTAGCTCTGTTATGCACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTGGATTGGATATATTAATCCTTACAATGATGGTACTAAGTACAATGAGAAGTTCAAAGGCAAGGCCACACTGACTTCAGACAAATCCTCCAGCACAGCCTACATGGAACTCAGCAGCCTGACCTCTGAGGACTCTGCGGTCTATTACTGTGCAAAAGGGGGTAACGATGGCTACTGGGGCCAAGGCACTACTCTCACAGTCTCCTCAAntibody G2 light chain variable region nucleotide sequence (SEQ ID NO: 28)GAAATTGTGCTCACCCAGTCTCCAACCACCATGGCTGCATCTCCCGGGGAGAAGATCACTATCACCTGTAGTGCCAGCTCAAGTATAAGTTCCATTTACTTGCATTGGTATCAGCAGAAGCCAGGATTCTCCCCTAAAGTCTTGATTTATAGGGCATCCAATCTGGCTTCTGGAGTCCCAGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATTGGCACCATGGAGGCTGAAGATGTTGCCACTTACTACTGCCAGCAGGGTAGTACTATACCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAAAntibody G2 heavy chain full antibody amino acid sequence (not including Fc domain)(SEQ ID NO: 29)EVQLQQSGPELVKPGASVKMSCKASGYTFTSSVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCAKGGNDGYWGQGTTLTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDAntibody G2 light chain full antibody amino acid sequence (SEQ ID NO: 30)EIVLTQSPTTMAASPGEKITITCSASSSISSIYLHWYQQKPGFSPKVLIYRASNLASGVPARFSGSGSGTSYSLTIGTMEAEDVATYYCQQGSTIPFTFGSGTKLEIKRADAAPTVSIFPPSSEQLTSGGASWCFLNNFYPRDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNECAntibody G2 heavy chain full antibody nucleotide sequence (not includinq Fc domain) (SEQID NO: 31) GAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGATACACATTCACTAGCTCTGTTATGCACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTGGATTGGATATATTAATCCTTACAATGATGGTACTAAGTACAATGAGAAGTTCAAAGGCAAGGCCACACTGACTTCAGACAAATCCTCCAGCACAGCCTACATGGAACTCAGCAGCCTGACCTCTGAGGACTCTGCGGTCTATTACTGTGCAAAAGGGGGTAACGATGGCTACTGGGGCCAAGGCACTACTCTCACAGTCTCCTCAGCCAAAACGACACCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTCAGTGACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATAntibody G2 liqht chain full antibody nucleotide sequence (SEQ ID NO: 32)GAAATTGTGCTCACCCAGTCTCCAACCACCATGGCTGCATCTCCCGGGGAGAAGATCACTATCACCTGTAGTGCCAGCTCAAGTATAAGTTCCATTTACTTGCATTGGTATCAGCAGAAGCCAGGATTCTCCCCTAAAGTCTTGATTTATAGGGCATCCAATCTGGCTTCTGGAGTCCCAGCTCGCTTCAGTGGCAGTGGGTCTGGGACCTCTTACTCTCTCACAATTGGCACCATGGAGGCTGAAGATGTTGCCACTTACTACTGCCAGCAGGGTAGTACTATACCATTCACGTTCGGCTCGGGGACAAAGTTGGAAATAAAACGGGCTGATGCTGCACCAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAGAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAACGACAAAATGGTGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACATTGACCAAGGACGAGTATGAACGACATAACAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATCGTCAAGAGCTTCAACAGGAATGAGTGTTAA

1. A method for preventing and/or treating inflammatory pain and/orsymptoms of inflammatory pain, comprising peripheral administration tothe individual of an effective amount of an anti-CGRP antagonistantibody.
 2. The method according to claim 1, wherein the medicament isprepared to be peripherally administered.
 3. The method according toclaim 1, wherein the medicament is administered peripherally.
 4. Themethod according to claim 1, wherein the medicament is prepared to beadministered orally, sublingually, via inhalation, transdermally,subcutaneously, intravenously, intra-arterially, intra-articularly,peri-articularly, locally and/or intramuscularly.
 5. The methodaccording to claim 4, wherein the medicament is prepared to beadministered subcutaneously or intravenously.
 6. The method according toclaim 1, wherein the anti-CGRP antagonist antibody acts peripherally onadministration.
 7. The method according to claim 1, wherein theinflammatory pain is arthritic pain.
 8. The method according to claim 7,wherein the arthritic pain is osteoarthritis pain.
 9. The methodaccording to claim 1, wherein the anti-CGRP antagonist antibody: (a)binds to CGRP; (b) blocks CGRP from binding to its receptor; (c) blocksor decreases CGRP receptor activation; (d) inhibits blocks, suppressesor reduces CGRP biological activity; (e) increases clearance of CGRP;and/or (g) inhibits CGRP synthesis, production or release.
 10. Themethod according to claim 1, wherein the anti-CGRP antagonist antibody:(i) is a human antibody, (ii) is a humanized antibody, (iii) is amonoclonal antibody, (iv) binds CGRP with a Kd of 50 nM or less (asmeasured by surface plasmon resonance at 37° C.); and/or (v) has a halflife in-vivo of at least 7 days.
 11. The method according to claim 1,wherein the anti-CGRP antagonist antibody specifically binds to theC-terminal region of CGRP.
 12. The method according to claim 10, whereinthe anti-CGRP antagonist antibody specifically recognises the epitopedefined by the sequence GSKAF.
 13. The method according to claim 1,wherein the anti-CGRP antibody comprises a VH domain that is at least90% identical in amino acid sequence to SEQ ID NO: 1 or
 19. 14. Themethod according to claim 1, wherein the anti-CGRP antibody comprises aVL domain that is at least 90% identical in amino acid sequence to SEQID NO: 2 or
 20. 15. The method according to claim 14, wherein theanti-CGRP antibody further comprises a VH domain that is at least 90%identical in amino acid sequence to SEQ ID NO: 1 or
 19. 16. The methodaccording to claim 1, wherein the anti-CGRP antibody comprises at leastone CDR selected from the group consisting of: (a) CDR H1 as set forthin SEQ ID NO: 3 or 21; (b) CDR H2 as set forth in SEQ ID NO: 4 or 22;(c) CDR H3 as set forth in SEQ ID NO: 5 or 23; (d) CDR L1 as set forthin SEQ ID NO: 6 or 24; (e) CDR L2 as set forth in SEQ ID NO: 7 or 25;(f) CDR L3 as set forth in SEQ ID NO: 8 or 26; and (g) variants of L1,L2 and H2.
 17. The method according to claim 1, wherein the anti-CGRPantibody comprises a VH domain that is at least 90% identical in aminoacid sequence to SEQ ID NO: 1 and a VL domain that is at least 90%identical in amino acid sequence to SEQ ID NO:
 2. 18. The methodaccording to claim 1, wherein the anti-CGRP antibody comprises a heavychain produced by the expression vector with ATCC Accession No.PTA-6867.
 19. The method according to claim 1, wherein the anti-CGRPantibody comprises a light chain produced by the expression vector withATCC Accession No. PTA-6866.
 20. The method according to claim 1,wherein the anti-CGRP antibody is produced by the expression vectorswith ATCC Accession Nos. PTA-6867 and PTA-6866. 21-31. (canceled)